A decision point between transdifferentiation and programmed cell death priming controls KRAS-dependent pancreatic cancer development

Nat Commun. 2025 Feb 19;16(1):1765. doi: 10.1038/s41467-025-56493-7.

Abstract

KRAS-dependent acinar-to-ductal metaplasia (ADM) is a fundamental step in the development of pancreatic ductal adenocarcinoma (PDAC), but the involvement of cell death pathways remains unclear. Here, we show that key regulators of programmed cell death (PCD) become upregulated during KRAS-driven ADM, thereby priming transdifferentiated cells to death. Using transgenic mice and primary cell and organoid cultures, we show that transforming growth factor (TGF)-β-activated kinase 1 (TAK1), a kinase regulating cell survival and inflammatory pathways, prevents the elimination of transdifferentiated cells through receptor-interacting protein kinase 1 (RIPK1)-mediated apoptosis and necroptosis, enabling PDAC development. Accordingly, pharmacological inhibition of TAK1 induces PCD in patient-derived PDAC organoids. Importantly, cell death induction via TAK1 inhibition does not appear to elicit an overt injury-associated inflammatory response. Collectively, these findings suggest that TAK1 supports cellular plasticity by suppressing spontaneous PCD activation during ADM, representing a promising pharmacological target for the prevention and treatment of PDAC.

MeSH terms

  • Animals
  • Apoptosis* / genetics
  • Carcinoma, Pancreatic Ductal* / genetics
  • Carcinoma, Pancreatic Ductal* / metabolism
  • Carcinoma, Pancreatic Ductal* / pathology
  • Cell Line, Tumor
  • Cell Transdifferentiation* / genetics
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • Mice, Transgenic
  • Necroptosis / genetics
  • Organoids / metabolism
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / metabolism
  • Pancreatic Neoplasms* / pathology
  • Proto-Oncogene Proteins p21(ras)* / genetics
  • Proto-Oncogene Proteins p21(ras)* / metabolism

Substances

  • Proto-Oncogene Proteins p21(ras)
  • MAP kinase kinase kinase 7
  • MAP Kinase Kinase Kinases
  • Hras protein, mouse
  • KRAS protein, human